This project deals primarily with the hormonal antihypertensive function of the renal papilla and its renomedullary interstitial cells (RIC). The antihypertensive neutral renomedullary lipid (ANRL) has been identified as the hormone mediating this function. This is an ideal antihypertensive substance since it decreases heart rate (HR) and suppresses sympathetic activity (SA) as it lowers the arterial pressure (AP). ANRL has been found in the renal venous effluent (in the blood) after unclipping the hypertensive Goldblatt animal. As the AP is lowered under these conditions HR and SA are decreased. The project's long term objectives include the evaluation of ANRL as an antihypertensive agent in the long range treatment of the hypertension of various hypertensive models and to study the metabolism of this hormone in normotensive and various hypertensive states. The structure of ANRL is being elucidated. Various specifc aims include: 1) The development of a method for measuring ANRL in body fluids beginning with the 3H mass spectrometric method; 2) Using the technique of 1), to determine the turnover rate of ANRL, where destroyed and how, and to determine pathways of metabolism; 3) to determine the state of ANRL in various hypertensive states (is it deficient or relatively so?), 4) to evaluate its mode of action (central vs. peripheral); 5) to apply ANRL therapeutically to various hypertensive states, evaluating modes of administration and effects. Factors that stimulate or suppress the synthesis of ANRL by the kidney, slices of renal papilla and cultured RIC will be evaluated. Those factors known to operate within the kidney (angiotensin, aldosterone, ADH, PG's and kallekrein) will be particularly emphasized. As soon as feasible, ANRL will be symthensized and made available in pure form. At that time, toxicity studies will be conducted and an IND will be sought in order to enter into clinical trials.